The present invention concerns a process for the catalytic isomerization of Z-3-methylpent-2-en-4-yn-1-ol to E-3-methylpent-2-en-4-yn-1-ol, hereinafter referred to for brevity as the isomerization of xe2x80x9cZ-pentolxe2x80x9d to xe2x80x9cE-pentol.xe2x80x9d
The known acid-catalyzed allylic rearrangement of 3-methylpent-1-en-4-yn-3-ol affords in thermodynamic equilibrium an isomeric mixture of Z- and E-pentol in the ratio Z-:E-pentol of about 85:15. These stereoisomers can if desired be separated from each other by physical means, e.g. by fractional distillation, to afford each stereoisomer in relatively good purity. The stereoisomer produced and isolated in the larger proportion, i.e. Z-pentol, is a useful intermediate, e.g. for the manufacture of vitamin A, and the stereoisomer produced and isolated in the smaller proportion, i.e. E-pentol, is also a useful intermediate, in this case e.g. for the manufacture of astaxanthin, zeaxanthin and further carotenoids. The situation may be schematically illustrated as follows, whereby the formulae are presented by conventional line representation: 
According to the relative requirement for one or the other stereoisomer depending on the relative amounts of the carotenoid and vitamin A end products to be produced therefrom, there exists an economical need to shift the above equilibrium of E- and Z-pentol from the thermodynamic one, and to influence the stereoisomeric ratio of these two useful intermediates. It is seldom economically feasible to separate the stereoisomers from a mixture in the thermodynamic equilibrium (about 85:15 Z-:E-pentol) as above. Indeed, since Z-pentol is the thermodynamically more stable pentol product, a shifting of the equilibrium in the direction Z-xe2x86x92E-entails an input of energy which would be justified if the relative requirement for astaxanthin, zeaxanthin and further carotenoids significantly exceeds about 15% of the total of both isomers. In this case, for example, there exists a need for a process for isomerizing a mixture of Z- and E-pentol, e.g. one in thermodynamic equilibrium with a Z-:E-ratio of about 85:15, to one with an increased proportion, i.e. higher than about 15%, of E-pentol.
This need has been surprisingly achieved by the catalytic isomerization process of the present invention which involves the use of bromine radicals (Br.) as the catalyst for isomerizing Z-pentol to E-pentol in a mixture of both these stereoisomers.
One embodiment of the invention is a process for catalytically isomerizing Z-3-methylpent-2-en-4-yn-1-ol to E-3-methylpent-2-en-4-yn-1-ol is provided. This process includes contacting a stereoisomeric mixture containing Z-3-methylpent-2-en-4-yn-1-ol and E-3-methylpent-2-en-4-yn-1-ol with a source of bromine radicals in a two-phase reaction mixture having an aqueous phase and a stereoisomeric mixture phase, intermixing the reaction mixture, and heating the reaction mixture to a temperature from about xe2x88x9210xc2x0 C. to about 100xc2x0 C.
In principle any chemical system for generating the bromine radicals necessary for the performance of the catalytic isomerization process of the present invention may be utilized in the process, and each such chemical system gives rise to a particular embodiment of the process.
Common to all the chemical systems for generating bromine radicals is the actual source of bromine radicals, which is suitably an alkali metal or alkaline earth metal bromide, or ammonium bromide. As the alkali metal or alkaline earth metal bromide there comes into consideration particularly sodium or potassium bromide or, respectively, calcium or magnesium bromide. Preferably sodium bromide or potassium bromide is employed as the source of the bromine radicals.
The amount of such bromide salt employed relative to the amount of pentol starting material (mixture of Z- and E-pentols) is suitably about 0.2 mole to about 5 moles/mole, preferably about 0.2 mole to about 1 mole/mole, most preferably about 0.2 mole to about 0.5 mole/mole.
In one embodiment of the present invention, a salt of a heavy metal is used as the catalyst for promoting the generation of bromine radicals from the source thereof. Oxygen is generally used as an auxiliary agent for promoting the bromine radical generation. Examples of the heavy metals (cationic constituents) of these salts are titanium, vanadium, chromium, manganese, cobalt, nickel, zirconium, niobium, praseodymium, hafnium and lead. Examples of the anionic constituents of these salts are chloride, bromide, oxide, sulphate, oxychloride (OCl24xe2x88x92) and acetate. Specific examples of such heavy metal salts are titanous chloride (TiCl3), vanadium trichloride (VCl3), vanadium dioxide (V2O4), vanadium pentoxide (V2O5), chromic chloride (CrCl3), manganous bromide (MnBr2), manganese dioxide (MnO2), manganous sulphate (MnSO4), manganous acetate (Mn(OCOCH3)2), manganic acetate (Mn(OCOCH3)3), cobaltous bromide (CoBr2), nickelous bromide (NiBr2), zirconic oxychloride (ZrOCl2) niobium pentoxide (Nb2O5), praseodymium chloride (PrCl3), praseodymium oxide (Pr6O11), hafnium tetrachloride (HfCl4) and plumbous bromide (PbBr2). A heavy metal bromide is preferably used as the catalyst. Independently of the nature of the anion, manganese, especially manganous (Mn2+) salts, are preferably used as the catalysts.
The amount in moles of the heavy metal salt employed relative to the amount of pentol starting material (mixture of Z- and E-pentols) is suitably about 0.001 mole to about 0.5 mole/mole, preferably about 0.001 to about 0.3 mole/mole, most preferably about 0.01 to about 0.03 mole/mole.
As indicated above, oxygen is also generally used in the promotion of the bromine radical generation. As will be evident from the nature of the heavy metal salts, various oxidation potentials (levels) are represented by the metal ions in the salts, from as low as 2+, e.g. manganese(II) (manganous) in MnBr2, MnSO4 and Mn(OCOCH3)2, to as high as 4+, e.g manganese(IV) in MnO2, or even 5+, e.g. vanadium(V) and niobium(V) in V2O5 and Nb2O5, respectively. The function of the oxygen, if used, is to raise the oxidation level of the heavy metal cations to render them effective in generating the bromine radicals from the bromide anions present. Thus a relatively low concentration of heavy metal cations with a high oxidation level suffices to generate the bromine radicals. For example, Mn2+ ions can be elevated to Mn3+ ions with oxygen, and a relatively small amount of such Mn3+ ions enables the bromine radicals to be generated. Indeed, if heavy metal cations of a sufficiently high oxidation level are present at the outset, the presence of oxygen may be omitted. As a further example, Mn2+ ions are not able to generate bromine radicals from the bromide in the absence of oxygen, but Mn3+ ions can do this.
In those cases where oxygen is used as an auxiliary agent for the bromine radical generation, it can be used alone or in admixture with an inert gaseous component, e.g. with nitrogen in air. The oxygen gas or gas mixture, preferably containing at least 5 vol. % of oxygen, may be continuously passed through the two-phase reaction medium during the isomerization process. The rate of oxygen or oxygen mixture passage is about 5 l/h to about 200 l/h, preferably about 20 l/h to about 50 l/h. The technical means of oxygen passage is unimportant to the present process and may be achieved using conventional technical methodology, such as with a stirrer having jet outlets through which the oxygen is passed and released continuously into the stirred reaction medium. The oxygen gas or gas mixture can be used under pressure, suitably at a pressure up to a maximum of about 50 bar (5 MPa), which serves to accelerate the isomerization.
In the process of the present invention the mixture of pentol stereoisomers may form the pentol phase, or the stereoisomers may be dissolved in an essentially water-immiscible organic solvent. Such a solvent is suitably an alkane, e.g. pentane, hexane or heptane; an aromatic hydrocarbon, e.g. benzene or toluene; a chlorinated alkane, e.g. methylene chloride, chloroform or carbon tetrachloride; or an aliphatic ether, e.g. diethyl ether or diisopropyl ether. The aqueous phase serves to dissolve the alkali metal, alkaline earth metal or ammonium bromide, i.e. the source of the bromine radicals, and also the heavy metal salt. The aqueous phase may be an aqueous methanolic solution.
The catalytic isomerization process according to this first embodiment is effected in a pH range from about 0 to about 2.5. It has been established that on conducting the process at higher pH values, e.g. from about pH 2.5 to about pH 4.0, the yield of the desired E-pentol is increasingly reduced as the pH value is increased. The preferred pH range is from about 0.5 to about 1.
To adjust the pH value, the presence of a strong mineral acid, i.e. one with a pKa value of less than about 2, or of the organic acid, acetic acid, in the reaction medium is required. For this purpose there may suitably be used hydrochloric, hydrobromic, sulphuric, nitric or perchloric acid as the mineral acid, or, as mentioned above, acetic acid. The chosen acid is added in sufficient quantity, also if necessary during the initiated isomerization process, to bring or maintain the pH within the above range. If acetic acid is used, this is preferably approximately 50% aqueous acetic acid. Preferably hydrobromic acid is used as the strong mineral acid.
As mentioned above the catalytic isomerization process of the present invention is effected at temperatures from about xe2x88x9210xc2x0 C. to about 100xc2x0 C. If the first embodiment is used, the temperature range for both a batch and a continuous methodology is more suitably from about 0xc2x0 C. to about 70xc2x0 C., and in the case of a continuous methodology the temperature may even be suitably raised for short residence times of a few minutes to about 90xc2x0 C. Preferably the temperature is from about 40xc2x0 C. to about 60xc2x0 C.
The isomerization process according to the first embodiment can be conducted using conventional procedural methodology. One suitable procedure involves heating a mixture of the bromide salt, the heavy metal salt and the acid required for pH adjustment in water to the desired reaction temperature under intensive mixing, e.g. through stirring, and then adding the mixture of pentol stereoisomers, as such or in solution in the essentially water-immiscible organic solvent, and also starting the oxygen passage. Intensive stirring is continued during the isomerization.
After completion of the isomerization process there generally results a two-phase mixture of which the aqueous and the organic phases can be separated by conventional means. The aqueous phase contains essentially the heavy metal salt catalyst, the bromide salt and the acid, and can be reused if desired for further isomerization reactions with a new Z- and E-pentol mixture. If necessary, additional bromide salt is added and/or the pH is adjusted by addition of more acid. The organic phase contains essentially as the dissolved material the Z/E-isomeric mixture of increased E-isomer content compared with that of the starting pentol mixture. The organic phase can be washed with water to neutrality by conventional means, and the pure E- and Z-isomers can be isolated therefrom for example by fractional distillation. The isolated E- and Z-pentols can then be used as desired, especially for the production of astaxanthin, zeaxanthin and further carotenoids and, respectively, for the production of vitamin A.
In a further embodiment of the present invention, there is used as the catalyst for promoting the generation of the bromine radicals a strong peroxide-type oxidizing agent. More particularly, such a catalyst is an alkali metal or alkaline earth metal peroxomonosulphate, peroxoborate, peroxodisulphate or peroxodiphosphate, or the system hydrogen peroxide/alkali metal or alkaline earth metal sulphate. In each case, the alkali metal is suitably sodium or potassium, and the alkaline earth metal is suitably calcium or magnesium. Examples of these catalysts include potassium peroxomonosulphate, sodium peroxoborate, sodium peroxodisulphate, potassium peroxodisulphate, potassium peroxodiphosphate and hydrogen peroxide/sodium sulphate. The catalyst is preferably a peroxodisulphate or the system hydrogen peroxide/alkali metal or alkaline earth metal sulphate, most preferably the latter catalyst system.
The amount in moles of strong peroxide-type oxidizing agent (catalyst) used for the isomerization reaction relative to the amount of pentol starting material is suitably about 0.01 to about 0.5 mole/mole, preferably about 0.015 to about 0.2 mole/mole. In the case of the hydrogen peroxide/sulphate catalyst system the hydrogen peroxide is conveniently used in aqueous solution, preferably at concentration of about 30%, and the amount of sulphate salt employed is conveniently about 0.1 to about 50 mole % of the molar amount of pentol starting material.
In contrast to the first embodiment described above, the present embodiment does not require oxygen as an auxiliary agent for promoting the generation of the bromine radicals. Indeed, this embodiment can be effected in an inert atmosphere, e.g. nitrogen or argon.
In the present embodiment the isomerization process is conveniently carried out in a two-phase medium in which the aqueous phase contains essentially the dissolved alkali metal, alkaline earth metal or ammonium bromide, i.e. the source of the bromine radicals, and optionally also added acid for any necessary pH adjustment. The organic phase is formed from the mixture of pentol stereoisomers, which may optionally be dissolved in an organic solvent. The organic solvent may be a chlorinated alkane, e.g. methylene chloride, chloroform or carbon tetrachloride; a lower, especially C1-6-, alkanol, e.g. methanol, ethanol, isopropanol, n-butanol or tert. butanol; an aliphatic ketone, e.g. isobutyl methyl ketone; an aliphatic ester, e.g. ethyl acetate; acetonitrile; an organic carbonate, e.g. dimethyl carbonate; an alicyclic hydrocarbon, e.g. methylcyclohexane; or an aromatic hydrocarbon, e.g. toluene. The use of an organic solvent in the reaction medium appears to reduce this tendency of the pentol stereoisomers to decompose, and is also of advantage by facilitating the isolation of the product after the reaction.
Regardless of the use or not of an organic solvent to dissolve the mixture of pentol stereoisomers, the volume of water per mole of such pentol stereoisomer mixture is maintained at about 50 ml to about 800 ml of water/mole of pentol stereoisomer mixture, preferably about 50 ml to about 200 ml of water/mole of pentol stereoisomer mixture. If a low volume of water is used, i.e. about 50-100 ml, the temperature at which the isomerization reaction is conducted is suitably somewhat higher than if volumes above about 100 ml are used in order to compensate for the lower heat capacity of the reaction mixture.
The catalytic isomerization process according to this embodiment, and in contrast to the first embodiment, is less influenced by the pH of the reaction medium, and indeed can generally be effected in the broad pH range of about 0 to about 10. Accordingly, the addition of acid to the medium for adjustment of the pH is usually unnecessary. The preferred pH range is, however, from about 0 to about 7. By conducting the isomerization reaction in the neutral pH range, i.e. around pH 7, any partial decomposition of the pentol stereoisomers, which occurs to some extent in the acid pH range (less than pH 7), is considerably reduced. If pH adjustment is effected, the same kind of acid may be added to the reaction medium as set forth above for the previous embodiment.
The catalytic isomerization process of this embodiment for both a batch and a continuous methodology is suitably effected at temperatures from about xe2x88x9210xc2x0 C. to about 70xc2x0 C. In the case of a continuous methodology the temperature may even be raised for short residence times of a few minutes to about 100xc2x0 C., whereby the tendency of the pentol stereoisomers to decompose at such higher temperatures must be observed by not prolonging unnecessarily the heating in the upper temperature range. The catalytic isomerization process is preferably effected at temperatures from about 40xc2x0 C. to about 60xc2x0 C.
The isomerization process according to this embodiment may also be conducted using conventional procedural methodology. An especially suitable methodology includes heating the two-phase medium consisting of the mixture of pentol stereoisomers, water, the bromide salt and any acid required for pH adjustment to the desired reaction temperature under gasification with an inert gas, such as nitrogen or argon, and under intensive mixing, e.g. through stirring, and then adding the catalyst as a crystalline solid or in aqueous solution. In the case of using the hydrogen peroxide/alkali metal or alkaline earth metal sulphate system as the catalyst, the above especially suitable methodology differs in that the sulphate is included in the two-phase medium for heating under gasification and intensive mixing to the desired reaction temperature. Then the hydrogen peroxide in aqueous solution is added. In all cases, the reaction mixture is suitably mixed further, e.g. by stirring, and if necessary, the pH adjusted periodically, until it has been established that the isomerization process has proceeded to a constant isomerization equilibrium or a substantially constant equilibrium. Thereafter, the mixture is suitably cooled, preferably to room temperature or thereabouts, and the isolation of the product effected.
After completion of the isomerization process according to this further embodiment there results a two-phase mixture with, in certain cases, a solid residue consisting of the insoluble salts, such as various sulphates, hydrogen sulphates etc. Any solid constituents can be readily removed, e.g by filtration. The remaining two-phase liquid medium containing the Z/E-isomeric mixture of pentols with increased E-isomer content in the organic phase and an aqueous phase containing the remaining dissolved salts are then treated essentially as described above in connection with the final isolation procedure of the first embodiment to afford the isolated E- and Z-pentols. In this case, too, the aqueous phase containing dissolved salts, or the salts isolated therefrom, can be reused if desired for further isomerization reactions with a new Z- and E-pentol mixture.
Regardless of the embodiment employed, the length of time required to achieve isomerization equilibrium depends on the particular reaction conditions employed, and can amount to a few minutes to several hours. As an example, in certain instances of the isomerization process being conducted at about 85xc2x0 C. using the two-phase solvent system water and methylene chloride, the isomerization equilibrium is rapidly achieved, i.e. within about 2 minutes. In any event, such reaction conditions as the concentration of the bromide salt and the employed amount of catalyst exert a strong influence on the reaction duration.